Knocked Up Podcast - Could IVM be the future of fertility care? With Dr Violet Kieu
In our latest Knocked Up podcast episode we are joined by fertility specialist Dr. Violet Kieu to explore IVM—In Vitro Maturation—a promising alternative to IVF.
In our latest Knocked Up podcast episode we are joined by fertility specialist Dr. Violet Kieu to explore IVM—In Vitro Maturation—a promising alternative to IVF.
Unlike IVF, IVM collects immature eggs and matures them in the lab, offering a shorter, less medicated (read injections) and more affordable fertility treatment. IVM could be ideal for women with high egg counts, PCOS, or those needing urgent fertility preservation before cancer treatment.
We also explore Kappa IVM, an exciting new variation showing comparable success rates to IVF with fewer side effects.
Is IVM right for you or someone you know? Tune in to learn how this evolving technology could transform fertility care in Australia.
TRANSCRIPT
Jordi Morrison: Hello and welcome to Knocked Up, the podcast about fertility and women's health. You are joined as always by me, Jordi Morrison and Dr. Raelia Lew, CREI Fertility Specialist. Welcome, Raelia.
Dr. Raelia Lew: Hi, Jordi. And we are also joined today by CREI Specialist Dr. Violet Kieu. Welcome, Violet.
Dr. Violet Kieu: Hello, thank you for having me.
Jordi Morrison: Thank you, Violet. So you're also a fertility specialist. And you specialize in reproductive endocrinology, fertility preservation, and a new technology that you're going to talk to us about today.
Dr. Violet Kieu: Absolutely. That's right. So as a fertility specialist, my interests are broadly in education and improvement. And something that I've been looking at a little bit more over the last few years has been IVM, in vitro maturation.
Jordi Morrison: Yeah, a new acronym for us. To understand the difference between IVF and IVM, it would be good to get a refresher on the egg cell. Violet, can I ask you to describe for our listeners how an egg cell is made, what happens to an egg cell over the course of our lives, and how it ultimately matures to make a baby?
Dr. Violet Kieu: Yes. So trying to unpick the mysteries inside the ovary or egg development is very complex. But in a nutshell, a woman is born with all the eggs she will ever have. And these are unique cells that are made when we are fetuses ourselves inside our mothers. These cells are in suspended animation. So these egg cells, and a single egg is the largest cell in the human body, this cell lives inside a follicle. And a follicle is simply supportive ovarian cells. If you think of the ovaries like a sponge, inside the little sponge hole is a house and an egg sits inside there. An egg is immature and it's held in suspended animation until it's asked to ovulate.
Egg is asked to ovulate. There are hormones that act on the follicle. The follicle grows and we can see that increase in size from a few millimeters to a centimeter and more. And then we know that the supportive cells are making nutrients and fluids to bathe that egg cell. And then ovulation is when the brain sends a trigger and that egg pops or bursts from that follicle or bursts in search of sperm to fertilize or not. Now, when an egg is asked to ovulate, it matures and that maturation is so fascinating because... in suspended animation, that egg cell has 46 chromosomes like any other cell in the human body. But when it's asked to mature, it releases half of its DNA so that that mature egg cell only has 23 chromosomes. And that's important because we are half mom, half dad. So once you have that egg cell with 23 chromosomes mixing with the sperm, then you have that new embryo. So that's an egg cell, immature held in the ovary until it's matured to meet sperm.
Jordi Morrison: And IVM has been in the media on and off over the last 10 years as a breakthrough technology in IVF. For our listeners, Violet, can you break down what is IVM?
Dr. Violet Kieu: So yes, IVM in its most basic form is collecting immature eggs from a woman and maturing them outside of the human body. And this is different to IVF, where we usually stimulate a woman to produce mature eggs and collect those already matured eggs.
Jordi Morrison: And so, Violet, in essence, in IVF, because we mature eggs in the body of a woman, we need to use a fairly significant course of medication to achieve that goal hormonally. Tell us what a woman goes through alternatively in the process of collecting immature eggs.
Dr. Violet Kieu: Yes. So in IVM, collecting immature eggs, some of the advantages have been reduced time because we don't use as many or as long hormone injections. It may also reduce costs because we are not using those medications, but also it... decreases the number of ultrasounds a woman may have in her cycle, the number of nursing appointments, the number of blood tests that she may have, and also reduces opportunity costs, the time otherwise that she might be doing something else. And IVM may be safer because we don't stimulate with the high-dose hormones for women who might be at higher risk of ovarian hyperstimulation syndrome.
Dr. Raelia Lew: Up to 10 days, two weeks of daily, usually, follicle-stimulating hormone injections that we do two or three ultrasounds to look at the follicles get larger. In IVM, we can use no days of injections. Or some protocols use two to three days of injections before the immature egg collection. So it really is a lot shorter.
Jordi Morrison: So Violet, I think, you know, there'll be listeners out there who are saying, hey, that sounds great, count me in. But one thing I think is quite commonly and probably a misconception in the media are direct comparisons of IVM and IVF in terms of outcomes and success rates for the average patient. Can you talk to who is IVF for? Who is IVM for? Why would a patient choose one pathway or another? And what are the successes we've seen so far in countries around the world and in Australia with IVM?
Dr. Violet Kieu: Yeah. What I would say about IVM and IVF is it's not comparing apples with apples. They are different modalities. IVM, the negatives thus far are that there is a lower overall or cumulative pregnancy or live birth rate. And that is because we do get less eggs and thus less embryos from an IVM cycle compared to an IVF cycle.
We would say, though, is that it offers choice and IVM could be thought of as another option in the armamentarium or in the ladder of assisted reproductive technologies. So does it potentially have a place between intrauterine insemination, IVM, all the way up to our strongest technology, which is IVF?
How... developing in the world, I'll tell you a little story about the first time I got involved in understanding about IVM. Australia, we were fortunate enough to host the ASPIRE, the Asia-Pacific Conference on Reproductive Endocrinology, and that was in 2023. And that was in Adelaide. And there was a group from Vietnam who had done the first randomized control study comparing a new form of IVM called kappa IVM versus IVF.
And I will explain kappa IVM a little bit later. But really what their randomized control study, so it was... sort of head-to-head comparing the two modes, they found that with the first embryo transfer, there was no difference. So IVM was not inferior in the live birth rate, which was 35% with the first embryo transfer. But overall, they would have to say that IVM was not as quote-unquote successful because there are less embryos in the IVM group.
That meant, though, was that for the first time in this presentation, there had been enough women going through this new technology to show that it was a viable option for people who may choose, again, for safety reasons, if they have a higher number of eggs, such as those with polycystic ovarian syndrome, or if they have been born with a high, we call it antral follicle count, or high antimal hormone, or high... egg count. So they showed that there were no cases of ovarian hyperstimulation syndrome in the IVM group. And over many papers now, since those 2020 years, there have been up to five big studies or five studies, albeit from the same group, but they have shown that there's been no cases of ovarian hyperstimulation syndrome. So from that point of view, that is an advantage of IVM.
I want to talk about kappa IVM. In the past, IVM has not been so successful because of the few number of eggs. And these immature eggs, it's been hard to mature them outside of the body. But what they found in research over the last few decades is that the breakthrough is that they've understood that when we collect an egg out of the ovary, it comes in the form of what's called a COC, cumulus oocyte complex, which essentially means support cells that look like a cloud, cumulus, that supports the egg. When we take the support cells and the eggs out of the body, the support cells stop supporting the egg. And when we take the immature egg out, that means that the egg can then start to mature. But it might do so in a way that is not controlled. And so now with kappa IVM, what the Vietnam group that have been involved with a group in Brussels is that they use a pre-IVM step where they can help support the supporting cells to help prevent the early genetic maturation for one day of the immature cell to allow time for the cellular machinery or all these other things inside the cytoplasm, inside the cell, to mature just that little bit extra before they allow the cell to mature. So that actually means that the egg has greater capacity, greater quality, greater ability to fertilize with a sperm to become an embryo. And that's where that 2022-2023 presentation has really shown more promise in IVM.
Jordi Morrison: You mentioned a trip to Vietnam, and I've actually got a lot of questions out of what you've just said. But from your trip to Vietnam, what did you see in terms of how another country approached fertility treatment?
Dr. Violet Kieu: Yeah, absolutely. So at that 2023 conference in Adelaide, I asked a question, stood up in the audience, and one of the conveners actually allowed me to talk to one of the presenter afterwards, and other colleagues in my fertility unit also had contact with the Vietnam unit. Thus in 2024, we had an opportunity and were invited and able to attend the unit in Vietnam, which was amazing. What it was, was to see how they also were not at all saying that IVM was going to replace IVF, that it was simply just another arrow in the bow of arrows, just another option. But what it did mean was clear patient selection. So again, those with the higher egg count, and it meant increase or different learning for both the clinician and the scientist. So our group, my fertility unit, was both scientists as well as clinicians.
So actually, IVM would require a bit of training because we are now collecting immature eggs from teeny tiny follicles, from follicles which were between two to nine millimeters. And in IVF, we're actually trying to get larger follicles. Some would say roughly 17 millimeters as an aim. So we are collecting from such a small size. And that does mean different training because if you have a... an unstimulated ovary or just an ovary stimulated for two to three days. It might be more mobile. You might also be using a different type of needle, for example, a thinner needle to get inside those smaller follicles. But that means precision. That means any bleeding could cause blood clots and clot up your thin needle. And what we found that they had used was what was called a double lumen needle.
So think of a needle and then think of an even tinier needle that goes through that needle. So like a sheath or... a guard around a needle. So that first needle they would put into the ovary when a patient's asleep and safely under ultrasound guidance to fix the ovary and then put that thinner needle inside it to direct it inside the follicle to gently draw out the fluid containing the immature egg. So that was one thing. And it was also a different technique because they would cure it, which means they would twist the needle all through the time to really try and collect that immature or little egg inside the follicle, especially if it was tucked away inside the wall of that follicle. So that was one thing that was done.
But then the second thing was sort of the magic in the lab that usually we have, my experience in Australia, we have one scientist collecting the fluid and meticulously collecting the eggs out of that fluid. In Vietnam, they had three scientists all sitting next to each other because in IVM, they had an extra step where they used a cell strainer. And that's not what is commonly done in IVF. But they would collect the fluid and they would strain it several times to remove, you know, blood clots, etc. But also to make sure that they were not missing these very small immature eggs. So that was what was different, the patient selection, doctor training and science behind the IVM.
Jordi Morrison: That's really interesting. And I think, Violet, one question that you and I probably get quite often whenever in the media new technologies are discussed is kind of from our patients who unfortunately are in a poor prognosis category and IVF looking for that amazing new technology that might make the difference for them. How would IVM be considered, just for our listeners, education for those patients, for your older patients, for your lower ovarian reserve patients? How would IVM stand up to traditional IVF in those cohorts?
Dr. Violet Kieu: I think... you look at the research, the research has been done in the subsection of high egg count, high follicle numbers, and the PCOS women, that there are some studies, less large numbers for those for fertility preservation. For example, in a cancer population. So they might require chemotherapy or cancer treatments quite soon. And so this shorter time to immature egg collection might be something that one can fit in before and without delaying their cancer treatments. So I'd say there are not large studies in the older population, in the lower egg count women at this stage. I think that's something we just have to see what the evidence tells us from that.
I might introduce though is that other questions around IVM has been around its safety and actually the evidence shows that with this new kappa IVM where there's that step of the immature egg collected delayed for 24 hours so that the cellular machinery can catch up to the genetics before it's used in usual IVF processes such as ICSI, intracytoplasmic sperm injection, embryo freeze, and then replacement. What we have seen in the data is that there's more than 800 babies now born from this newer kappa IVM technology. And they have shown safety for women, embryos, and children.
So for women, no cases of ovarian hyperstimulation syndrome. In terms of for the embryos, there have been studies to look at the genetics, so to do the pre-implantation genetic testing to look for aneuploidy or different number of chromosomes, and it is no different to a population compared to IVF. They've also looked at... epigenetics, which is the signaling around the DNA. They've been able to look at that. And that is also no different to IVF embryos. And finally, for children, they've had two-year follow-up and used sort of accredited or pediatric developmental scoring systems and have found that the IVM children, or the CAPA, the newer IVM children are no different to conventional IVF. And also they did a comparison with spontaneously or naturally conceived children with no developmental differences as well. So we can say that in different studies, there is safety of IVM, but yes, you're right. We don't have all the subgroups for who it may be useful for.
Dr. Raelia Lew: Yeah. And look, I think it's really interesting. In IVF, we've got about 13 million births worldwide over the last 40 plus years of evolving therapy. So while I think safety data is really, really reassuring, it probably is fairly early days to be able to pick up rare things. I think some of the things we see in IVF that have a slightly higher risk epigenetically, like for example, imprinting disorders, Angelman syndrome, et cetera, they have a one in 200,000 incidence in IVF. So even though that's more than background, it's still very, very rare. So we probably do need more births to conclusively discuss safety and also over a longer period of time. But I think it's really reassuring that initial data is... showing no differences to babies born in other ways.
Dr. Violet Kieu: Yes, absolutely. And I do think it's important that we do have data, not just increased numbers, but from different units around the world as well. So that's something that is important to cross-correlate data.
Jordi Morrison: I think, Violet, also you raised some really interesting points about surgical skill sets and the different ways of kind of learning how to do that. Does, I guess, show some significant changes of practice to what we're used to in Australia in IVF teams. What does it take to introduce IVM to a unit in Australia?
Dr. Violet Kieu: That's a big question. I think that's a really, really big question because that goes back to introducing any new technique to a unit. So we've already talked about things such as training, safety, but even to go back. So going back to where IVM sits now, there are different worldwide guidelines that say that IVM is no longer experimental. So that's from the American Society of Reproductive Medicine have said that, as well as ESHRE, the European Society. That's more particular in the fertility preservation guideline that they've written. So it's a small emerging technology that's no longer experimental, and the ESHRE has said it's innovative. So it's still new. What it would mean is to have clear oversight. As it stands, the IVM media in Australia is not an approved product. So that would mean you'd have to go to the Australian government through the Therapeutic Goods Administration Unit to apply to use the product, that is the newer culture medias for IVM.
And that would be under guidance. So reporting every six months, what the patient selections, what are the outcomes, and of course, immediate reporting within 24 hours of any adverse events that have occurred or may have occurred as a result. So it takes a lot of oversight to do that. And I wouldn't think that that's something that a person does in isolation. It would be within a unit with clinicians and scientists who have had training, for example, overseas or have research interests in this so that it's done in a clear manner and that any outcomes are reported for the betterment of all of our understanding and for the safety of the couples, women and children involved. So initially, I think that would probably represent concentration of expertise amongst a small group of clinicians within a unit and then potentially after proof of safety and proof of efficacy later out rolling that to training other clinicians within a unit.
Dr. Raelia Lew: Yeah, absolutely. And if I can offer a parallel, you and I, both being CREI accredited fertility specialists, we train junior doctors all the time. And when we have a new junior doctor who may come to our unit or to a public unit, there are things that we do. So, right, do 20, do 50 scans before vaginal scans. Show me that you can see the ovaries. Show me you can see a follicle. Before then, we'll show them how we do an egg collection in theatre, then supervise them doing it before that they can do it themselves independently. So definitely, I think in medicine, there is a strong culture of teaching and having accredited steps to gain mastery in a skill set.
Jordi Morrison: And what's next for IVM? Again, another big question. So many big questions.
Dr. Violet Kieu: I would say IVM is a concept. It's a concept of taking immature eggs outside of... then creating a microenvironment to mature them so that things, as I've mentioned, can be an alternative for a woman that could potentially be safer, lower intervention, more convenient for her and less intervention. So the future then becomes how do we best recreate this microenvironment? There are different groups over the world who are looking at this. The one group that, because of our connection in Adelaide and in Vietnam and in Brussels, has been the Kappa IVM, that capacitation IVM with that 24 hours, just that pause to allow the whole cell to mature before moving on. That's only one type of IVM because I would say that even IVF, there's not one type of IVF. There's not one protocol. There are different ways of managing a cycle. So the future of IVM is... the science, the microenvironment. There are other groups who don't use that capacitation step. There are other groups who collect immature eggs and actually think of something completely different, not putting in growth factors or hormones into the media to develop the egg, but actually using other cells. So that actually can be co-culture with other cells that mimic the ovarian supportive cells to create that microenvironment. So that actually is out there as well.
But the future would be, as Raelia has mentioned, what other subgroups of people or patients may benefit from IVM? And I've alluded to the fertility preservation group, people who might unfortunately need treatment for cancer quite quickly and that a conventional IVF cycle might take too long before they have their cancer treatment and their chemo treatment can affect delicate cells such as egg cells. And that's why we do want to sometimes preserve eggs before chemotherapy, if possible. And the other group, I guess, would be could IVM revolutionize our understanding of egg freezing? Because if there could be a way where with no medication at any day of the week, a woman in her reproductive years who wishes to freeze her eggs could walk into or plan an egg collection, again, with less hormones, less risk of ovarian hyperstimulation syndrome, that would be one way of directing IVM to egg freezing.
Dr. Raelia Lew: Yeah, less cost, Violet.
Dr. Violet Kieu: Yes, less cost for the patient. A lot less cost. Yeah. Because the drugs are expensive. So in egg freezing currently, where we mature eggs in the body, the drugs for an egg freezing cycle where it's not Medicare covered cost quite a lot of money to the patient, usually somewhere in the realm of one and a half to three thousand dollars depending on what's prescribed. And that's what our government pays even though patients don't feel that cost because they're not out of pocket. That's what the government pays every time a person does an IVF stimulated cycle with Medicare. So that would be a way in an ideal world that if women came young enough, because they'd have to come when they were young, I think for IVM to be a sustainable idea for egg freezing, they'd need to come probably in their 20s where their egg count is high enough that you would be able to get a reasonable outcome from IVM with someone without a polycystic ovary, a PCOS style ovary. But yeah, definitely. It's really cool. I think we would love to do some research long-term once we get IVM more mainstream on the egg freezing cohorts of young women who don't have fertility problems to see if... Maybe 10 years from now, that would be a viable option, would be a good one.
Dr. Raelia Lew: Yeah, I do agree. What I'd say, and I wanted to also share this other story, is that the story of IVM isn't super new. It actually precedes or is older than IVF. What we do know is that there were the trio of Robert Edwards, of Patrick Steptoe and Jean Purdy, whose work led to the birth of the first IVF baby, Louise Brown, in 1978. But even the decade before that, in 1965, the scientist, Robert Edwards, was already publishing work in high-level journals such as Nature about looking at the development of the human egg and he was already looking at the development of immature eggs outside of the body. And of course, it's taking the science and technology now to recreate that microenvironment. But this idea is not new and it's something that was even looked at by one of the forefathers of IVF.
Jordi Morrison: Yeah, I think that's obviously very humbling and I think that a lot of ideas that we take for granted have a really long period of progress before they translate into tangible science.
Dr. Raelia Lew: Yes. So I think everybody should be very mindful of the fact that IVF is something that is continually evolving and we're really looking at the science behind the scenes. A lot of the scientists involved in the labs making babies are also passionate researchers. And, you know, they put in a lot of effort, time, energy and intellect to try to develop these processes. And it's often very slow rather than something that happens overnight.
Jordi Morrison: I actually was asked in a media interview the other day, what's new in IVF? And the journalist was really looking for something that we discovered yesterday, implemented tomorrow and it's going to change the world. And I think the timeline of these things is realistically, it takes decades, it takes... know, a village. It takes an international community to develop these ideas, to translate them into reality and then to validate them, prove safety and then, you know, take them, as you say, to things like TGA approval so that they can be implemented in a robust way in a country like Australia.
Dr. Raelia Lew: And isn't that amazing that we are able to build or stand on the shoulders of giants to pull our knowledge together and also as Australians be involved in international dialogue about IVF? I think that's really amazing.
Jordi Morrison: Yeah, absolutely. Thank you, Violet. We look forward to having you back in a few years to share the new research with us.
Dr. Violet Kieu: Yeah, brilliant. Thank you so much, Jordi. And thank you, Raelia, for your time and interest in this topic.
Jordi Morrison: To support Knocked Up, leave us a review or recommend to a friend. Join us on Instagram @knockeduppodcast and join Raelia @drraelialew. And email us your questions to podcast@womenshealthmelbourne.com.au.
Hosted by Dr Raelia Lew and Jordi Morrison
Dr Raelia Lew is a RANZCOG Board Certified CREI Fertility specialist, Gynaecologist and the Director of Women’s Health Melbourne.
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